GuestSpeak & ResearchSpeak: immunological checkpoints and MS

We have a new kid blogger on the block; welcome DrBenJ #GuestSpeak #ResearchSpeak #MSResearch #MSBlog

Ben is a junior doctor who has just started his foundation training at Whipps Cross University Hospital and the Royal London. He first became interested in Multiple Sclerosis as a medical student working with Gabe DeLuca’s group in Oxford. In the future he would like to split his time between working as a clinical neurologist and doing a combination of basic science and clinical research.

“Please note I am trying something new with this guest post and inserting the text as an embedded document. This allows the guest blogger to edit and make changes to the document without needing to logon to the blogger portal. Please let us know if this works for you? In addition, the Mouse Doctor has a lot to say about this post as well and I will get him to do a post on this topic later in the week or possibly next week.”

9 comments

Mouse CTLA-4-knockout appear to be unable to stop the immune response and developed a massive response of lymphocytes proliferation since, as explained MD, CTLA-4 is a negative regulator of the immune response, since CTLA-4 is linked to regulatory T cells then if there is no immune system also regulates T cells can proliferate wildly (that's what I understood).

Then according to the latest publications made here on the Blog, CTLA-4 blocking would be more related to the phenotype of MS linked to more brain lesions than bone marrow? or not?

I became intrigued by reading the Belatacept (another fusion protein of the CTLA-4 antibodies) appears which is used in the treatment against EBV.I would like to understand what the relation between CTLA-4 and EBV …

Hi Cinara, this is a very interesting question. Blocking CTLA-4 does enhance the killer T cell response to EBV (e.g. http://www.ncbi.nlm.nih.gov/pubmed/27186886). An important question is whether this effect of boosting T cell activity is helpful. It could help to control EBV infection, but the result might be (as the Gerdes paper suggests) that there are more activated killer T cells in the brain and therefore more 'bystander damage'. The problem with immunological checkpoint inhibitors like abatacept and belatacept is that they interfere with the delicate balance between 'go' and 'stop' signals in the immune system in quite a crude way. I think the balance between controlling EBV infection and limiting collateral damage illustrates nicely why this line of therapy, while very exciting, is still in its early days. It will take a bit of time to get the balance right.

Hi Dr BenJAFAIK most of the therapies targeting cytokines and receptors failed miserably in MS. May be time to look downstream? E.g. NF-kB inhibitors, I wonder if anyone looks into this as not too much on pubmed

And from what I've read both Laquinimod as Teriflunomide seem to have more neuroprotective effect than actually immunomodulator or immunosuppressant, their results were the low as the control in reducing outbreaks of MS, it seems to help in the reduction of axonal damage but the action on the inflammatory process seems to be weak.